Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance
Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance
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DOI：
10.1152/ajpendo.00399.2006
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发表时间：
2007-10-01
影响因子：
5.1
通讯作者：
Cortright, Ronald N.
中科院分区：
文献类型：
--
作者：
Noland, Robert C.;Woodlief, Tracey L.;Cortright, Ronald N.
过氧化物酶体氧化产生被线粒体更有效利用的代谢物。这具有潜在的临床重要性，因为脂肪酸氧化减少被怀疑会促进肥胖相关胰岛素抵抗中的过量脂质积累。我们的目的是评估过氧化物酶体的贡献，线粒体氧化混合腓肠肌（MG），肝脏和左心室（LV）匀浆瘦和脂肪（FA/FA）Zucker大鼠。结果表明，使用各种脂质底物的完全线粒体氧化（CO2产生）在MG中增加约两倍，在LV中不变，在fa/fa大鼠的肝脏中减少约50%。在分离的线粒体中，丙二酰辅酶A抑制棕榈酸的CO2产生78%，而加入分离的过氧化物酶体抑制减少到21%。这些数据表明，过氧化物酶体产物可以独立于CPT I进入线粒体，从而提供了在丙二酰辅酶A水平升高的条件下维持脂质处置的途径，例如在胰岛素抵抗组织中。在fa/fa大鼠中，肝脏和MG（LV未改变）中二十四酸的过氧化物酶体代谢升高，但过氧化物酶体产物分布不同。不完全氧化的三倍升高是导致肝脏过氧化物酶体氧化增加的唯一原因（CO2未改变）。另外，只有二氧化碳被检测到MG，表明过氧化物酶体的产品被专门分配到线粒体完成脂质处置。这些数据表明过氧化物酶体衍生产物的组织特异性目的地，并强调了过氧化物酶体在肥胖、胰岛素抵抗状态下骨骼肌脂质代谢中的潜在作用。
Peroxisomal oxidation yields metabolites that are more efficiently utilized by mitochondria. This is of potential clinical importance because reduced fatty acid oxidation is suspected to promote excess lipid accumulation in obesity-associated insulin resistance. Our purpose was to assess peroxisomal contributions to mitochondrial oxidation in mixed gastrocnemius (MG), liver, and left ventricle (LV) homogenates from lean and fatty (fa/fa) Zucker rats. Results indicate that complete mitochondrial oxidation (CO2 production) using various lipid substrates was increased approximately twofold in MG, unaltered in LV, and diminished similar to 50% in liver of fa/fa rats. In isolated mitochondria, malonyl-CoA inhibited CO2 production from palmitate 78%, whereas adding isolated peroxisomes reduced inhibition to 21%. These data demonstrate that peroxisomal products may enter mitochondria independently of CPT I, thus providing a route to maintain lipid disposal under conditions where malonyl-CoA levels are elevated, such as in insulin-resistant tissues. Peroxisomal metabolism of lignoceric acid in fa/fa rats was elevated in both liver and MG (LV unaltered), but peroxisomal product distribution varied. A threefold elevation in incomplete oxidation was solely responsible for increased hepatic peroxisomal oxidation (CO2 unaltered). Alternatively, only CO2 was detected in MG, indicating that peroxisomal products were exclusively partitioned to mitochondria for complete lipid disposal. These data suggest tissue-specific destinations for peroxisome-derived products and emphasize a potential role for peroxisomes in skeletal muscle lipid metabolism in the obese, insulin-resistant state.